This application is a 371 of PCT/FR01/00509 filed Feb. 22, 2001.
A subject-matter of the present invention is novel 1,3-dihydro-2H-indol-2-one derivatives, a process for their preparation and the pharmaceutical compositions comprising them.
The compounds according to the present invention exhibit an affinity and a selectivity for arginine-vasopressin (AVP) V1b receptors or for both V1b and V1a receptors.
AVP is a hormone known for its antidiuretic effect and its effect in regulating arterial pressure. It stimulates several types of receptors: V1 (V1a, V1b) or V2. These receptors are located in particular in the liver, vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal glands, pancreas, central nervous system or pituitary gland. AVP thus exerts cardiovascular, heptatic, pancreatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system and on the uterine sphere.
The localization of various receptors is described in: S. Jard et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology, H. Imura and K. Shizurne ed., Experta Medica, Amsterdam, 1988, 1183-1188, and in the following articles: J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.
More particularly, AVP V1a receptors are located in numerous peripheral organs and in the brain. they have been cloned in the rat and man and they regulate the majority of known effects of AVP: platelet aggregation; uterine contractions; vessel contraction; the secretion of aldosterone, of cortisol, of CRF (corticotropin-releasing factor) and of adrenocorticotrophic hormone (ACTH); heptatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, and the like).
The V1b receptors were initially identified in the adenohypophysis of various animal species (rat, pig, cow, sheep, and the like), including in man (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. de Keyser et al., FEBS Letters, 1994, 356, 215-220), where they stimulate the release of adrenocorticotrophic hormone by AVP and potentiate the effects of CRF on the release of ACTH (G. E. Gillies et al., Nature, 1982, 299, 355). In the hypothalamus, the V1b receptors also induce a direct release of CRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these various respects, implicated in stress situations.
These V1b receptors have been cloned in the rat, man and mouse (Y. de Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S.J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22, 251-260) and various studies (in situ hybridization, PCR (Polymerase Chain Reaction), and the like) reveal ubiquitous localization of these receptors in various central tissues (brain, hypothalamus and adenohypophysis, in particular) and peripheral tissues (kidney, pancreas, adrenal glands, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, and the like) and in some tumours (hypophyseal or pulmonary tumours, and the like), suggesting a broad biological and/or pathological role of these receptors and potential involvement in various diseases.
By way of examples, in the rat, studies have shown that AVP, via the V1b receptors, regulates the endocrine pancreas, stimulating the secretion of insulin and of glucagon (B. Lee et al., Am. J. Physiol., 269 (Endocrinol. Metab. 32), E1095-E1100, 1995) or the production of catecholamines in the medulloadrenal, which is the site of a local synthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a), 3906-3914). Thus, in the last tissue, AVP, via these receptors, would have a crucial role in some types of suprarenal pheochromocytomas which secrete AVP and which, for this reason, bring about a sustained production of catecholamines which are the cause of hypertensions which are resistant to angiotensin-II receptor antagonists and to converting enzyme inhibitors. The adrenal cortex is also rich in V1a receptors involved in the production of gluco- and mineralocorticoids (aldosterone and cortisol). Via these receptors, AVP (circulating or synthesized locally) can bring about production of aldosterone with an effectiveness comparable to that of angiotensin II (G. Guillon et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol is a powerful regulator of the production of ACTH, the stress hormone.
Recent studies have also shown that the adrenal glands are capable of directly releasing CRF and/or ACTH via the activation of the V1b and/or V1a receptors carried by the cells of the medulla (G.
Mazzocchi et al., Peptides, 1997, 18(2), 191-195; E. Grazzini et al., J. Clin. Endocrinol. Metab., 1999, 84 (6), 2195-2203).
The V1b receptors are also regarded as a label for ACTH-secreting tumours, which are some pituitary tumours and some bronchial (small cell lung cancers or SCLC), pancreatic, adrenal and thyroid carcinomas, resulting in some cases in Cushing""s syndrome (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941). The V1a receptors are, for their part, a more specific label for small cell lung cancers (SCLC) (P. J. Woll et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73). Thus, the compounds according to the present invention are obvious diagnostic tools and offer a novel therapeutic approach in the proliferation and detection of these tumours, at an early stage too (radiolabelling; SPECT (Single Photon Emission Computed Tomography); PET Scan (Positron Emission Tomography Scanner)).
The lavish presence of the messenger of the V1b receptors in the stomach and intestine suggests involvement of AVP via this receptor in the release of gastrointestinal hormones, such as cholecystokinin, gastrin or secretin (T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurokawa and S. Yoshida ed., Elvesier Science, 1995, 409-413).
1,3-Dihydro-2H-indol-2-one derivatives have been disclosed in some patent applications as ligands of the arginine-vasopressin and/or oxytocin receptors: mention may be made of Patent Applications WO 93/15051, EP 636 608, EP 636 609, WO 95/18105, WO 97/15556 and WO 98/25901.
To date, no nonpeptide compound having an affinity and a selectivity for arginine-vasopressin V1b receptors or for both V1b and V1a receptors is known.
Novel 1,3-dihydro-2H-indol-2-one derivatives have now been found which exhibit an affinity and a selectivity for arginine-vasopressin V1b receptors or for both V1b and V1a receptors.
These compounds can be used for the preparation of medicaments of use in the treatment or prevention of any pathology where arginine-vasopressin and/or the V1b receptors or both the V1b receptors and the V1a receptors are implicated, in particular in the treatment or prevention of conditions of the cardiovascular system, for example hypertension, of the central nervous system, for example stress, anxiety, depression, obsessive-compulsive disorder or panic attacks, of the renal system or of the gastric system and in the treatment of small cell lung cancers, of obesity, of type-II diabetes, of insulin resistance, of hypertriglyceridaemia, of atherosclerosis, of Cushing""s syndrome or of any pathology resulting from stress and chronic stress conditions.
Thus, according to one of its aspects, the subject-matter of the present invention is compounds of formula: 
in which:
n is 0, 1 or 2 and p is 0, 1 or 2; the sum n+p being equal to 1 or 2;
R1 represents a halogen atom; a (C1-C4) alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; or a trifluoromethoxy-radical;
R2 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; or a trifluoromethyl radical;
or else R2 is in the 6-position of the indol-2-one ring and R1 and R2 together-represent the bivalent trimethylene radical;
R3 represents a halogen atom; a hydroxyl; a (C1-C2)alkyl; a (C1-C2)alkoxy; or a trifluoromethoxy radical;
R4 represents a hydrogen atom; a halogen atom; a (C1-C2)alkyl; or a (C1-C2)alkoxy;
or else R4 is in the 3-position of the phenyl and R3 and R4 together represent the methylenedioxy radical;
R5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; or a (C1-C2) alkoxy;
R6 represents a (C1-C4)alkoxy;
R7 represents a (C1-C4)alkoxy;
R8 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; or a (C1-C4)alkoxy;
R9 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; or a (C1-C4)alkoxy;
and their solvates and/or hydrates.
The compounds of formula (I) comprise at least 2 asymmetric carbon atoms. The optically pure isomers of the compounds of formula (I) and their mixtures in any proportion form part of the invention.
The term xe2x80x9chalogen atomxe2x80x9d is understood to mean a chlorine, bromine, fluorine or iodine atom.
The term xe2x80x9calkylxe2x80x9d or the term xe2x80x9calkoxyxe2x80x9d are respectively understood to mean a linear or branched alkyl or alkoxy radical respectively.
In the compounds of formula (I), the radical: 
represents one of the following radicals: 
According to the present invention, preference is given to the compounds of formula (I) in which:
n is 0, 1 or 2 and p is 0, 1 or 2; the sum n+p being equal to 1 or 2;
R1 represents a halogen atom; a (C1-C4) alkyl; a trifluoromethyl radical; or a trifluoromethoxy radical;
R2 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; or a trifluoromethyl radical;
or else R2 is in the 6-position of the indol-2-one ring and R1 and R2 together represent the bivalent trimethylene radical;
R3 represents a halogen atom; a hydroxyl; or a (C1-C2)alkoxy;
R4 represents a hydrogen atom; a halogen atom; a (C1-C2)alkyl; or a (C1-C2)alkoxy;
or else R4 is in the 3-position of the phenyl and R3 and R4 together represent the methylenedioxy radical;
R5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; or a (C1-C2) alkoxy;
R6 represents a (C1-C4)alkoxy;
R7 represents a (C1-C4)alkoxy;
R8 represents a hydrogen atom;
R8 represents a hydrogen atom;
and their solvates and/or hydrates.
According to the present invention, the compounds of formula (I) having an (A), (D) or (E) radical are preferred.
According to the present invention, preference is given to the compounds of formula (I) in which R1 represents a chlorine atom, a methyl radical or a trifluoromethoxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R2 represents a hydrogen atom or is in the 4- or 6-position of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical.
According to the present invention, preference is given to the compounds of formula (I) in which R3 represents a chlorine atom or a methoxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R4 represents a hydrogen atom or is in the 3- or 4-position of the phenyl and represents a methoxy radical; or else R4 is in the 3-position of the phenyl and together with R3 represent a methylenedioxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R5 represents a dimethylamino group, an azetidin-1-yl radical or a methoxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R6 is in the 2-position of the phenyl and represents a methoxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R7 represents a methoxy radical.
According to the present invention, preference is given to the compounds of formula (I) in which R8 and R8 each represent a hydrogen atom.
Preference is more particularly given to the compounds of formula (I) in which:
the 
xe2x80x83radical represents an (A), (D) or (E) radical;
R1 represents a chlorine atom or a methyl radical;
R2 represents a hydrogen atom or is in the 4- or 6-position of the indol-2-one and represents a chlorine atom, a methyl radical or a methoxy radical;
R3 represents a methoxy radical or a chlorine atom;
R4 represents a hydrogen atom or is in the 3- or 4-position of the phenyl and represents a methoxy radical;
or else R4 is in the 3-position of the phenyl and together with R3 represent a methylenedioxy radical;
R8 represents a dimethylamino group or a methoxy radical;
R6 is in the 2-position of the phenyl and represents a methoxy radical;
R8 represents a methoxy radical;
R8 and R8 represent a hydrogen atom;
and their solvates and/or hydrates.
According to the present invention, preference is given to the compounds of formula (I) in the form of optically pure isomers.
More particularly, preference is given to the optically pure isomers of the compounds of formula: 
in which n, p, R1, R2, R3, R4, R5, R6, R7, R8 and R8 are as defined for a compound of formula (I), the carbon atom carrying the COR5 substituent has the (S) configuration and the carbon atom in the 3-position of the indol-2-one has either the (R) configuration or the (S) configuration.
Preference is very particularly given to the levorotatory isomer of the compounds of formula (Ia).
The following compounds:
(3S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(1S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide, levorotatory isomer;
(2S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-2,3-dihydro-1H-indole-2-carboxamide, levorotatory isomer;
Methyl ester of (3S)-2-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, levorotatory isomer;
(3S)-2-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6,7-dimethoxy-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-3-(1,3-benzodioxol-4-yl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
(3S)-2-[4-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, levorotatory isomer;
and their solvates and/or hydrates are more particularly preferred.
According to another of its aspects, a subject-matter of the present invention is a process for the preparation of the compounds of formula (I), their solvates and/or their hydrates, characterized in that:
a compound of formula: 
xe2x80x83in which n, p, R1, R2, R3, R4, R5, R8 and R8 are as defined for a compound of formula (I), is reacted, in the presence of a base, with a halide of formula: 
xe2x80x83in which R6 and R7 are as defined for a compound of formula (I) and Hal represents a halogen atom.
The reaction is carried out in the presence of a strong base, such as a metal hydride, for example sodium hydride, or an alkali metal alkoxide, for example potassium tert-butoxide, in an anhydrous solvent, such as N,N-dimethylformamide or tetrahydrofuran, and at a temperature of between xe2x88x9270xc2x0 C. and +60xc2x0 C. The reaction is preferably carried out by using a compound of formula (III) in which Hal=Cl.
The compounds of formula (I) thus obtained can subsequently be separated from the reaction mixture and purified according to conventional methods, for example by crystallization or chromatography.
The compounds of formula (II) are prepared by the reaction of a 3-halo-1,3-dihydro-2H-indol-2-one compound of formula: 
in which R1, R2, R3 and R4 are as defined for a compound of formula (I) and Hal represents a halogen atom, preferably chlorine or bromine, with a compound of formula: 
in which n, p and R5, R8 and R9 are as defined for a compound of formula (I). The reaction is carried out in the presence of a base, such as diisopropylethylamine or triethylamine, in an inert solvent, such as dichloromethane, chloroform or tetrahydrofuran or a mixture of these solvents, and at a temperature of between ambient temperature and the reflux temperature of the solvent.
The compounds of formula (III) are known or prepared by known methods, such as those disclosed in EP-0 469 984 B and WO 95/18105. For example, the compounds of formula (III) can be prepared by halogenation of the corresponding benzenesulphonic acids or of their salts, for example of their sodium or potassium salts. The reaction is carried out in the presence of a halogenating agent, such as phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride, without a solvent or in an inert solvent, such as a halogenated hydrocarbon or N,N-dimethylformamide, and at a temperature of between xe2x88x9210xc2x0 C. and 200xc2x0 C.
2,4-Dimethoxybenzenesulphonyl chloride is prepared according to J. Am. Chem. Soc., 1952, 74, 2008. 3,4-Dimethoxybenzenesulphonyl chloride is commercially available or prepared according to J. Med. Chem., 1977, 20 (10), 1235-1239.
The compounds of formula (IV) are known and are prepared according to known methods, such as those disclosed in WO 95/18105.
For example, a compound of formula: 
in which R1, R2, R3 and R4 are as defined for a compound of formula (I), is converted into a compound of formula (IV) in which Hal=Cl by the action of thionyl chloride in the presence of a base, such as pyridine, in an inert solvent, such as dichloromethane, and at a temperature between 0xc2x0 C. and ambient temperature.
According to another example of the preparation of the compounds of formula (IV), a compound of formula: 
in which R1, R2, R3 and R4 are as defined for a compound of formula (I), is converted into a compound of formula (IV) by means of a halogenating agent, such as bromine, according to the process described in Farm. Zh. (Kiev), 1976, 5, 30-33.
The compounds of formula (VI) are known and are prepared according to known methods, such as those disclosed in WO 95/18105.
For example, a compound of formula (VI) is prepared by reaction of a 1H-indole-2,3-dione derivative of formula: 
in which R1 and R2 are as defined for a compound of formula (I), with an organomagnesium derivative of formula: 
in which R3 and R4 are as defined for a compound of formula (I) and Hal represents a halogen atom, preferably bromine or iodine, in an inert solvent, such as tetrahydrofuran or diethyl ether, and at a temperature of between 0xc2x0 C. and the reflux temperature of the solvent.
A compound of formula (VI) in which R3 is as defined for a compound of formula (I) and R4, which is other than hydrogen, is in the 3- or 6-position of the phenyl can also be prepared by the reaction of a compound of formula: 
in which R3 is as defined for a compound of formula (I) and R4 is in the 2- or 5-position of the phenyl, with a lithium derivative, such as n-butyllithium, and then the lithiated intermediate thus obtained is reacted with a compound of formula (VIII). The reaction is carried out in a solvent, such as diethyl ether, tetrahydrofuran, hexane or a mixture of these solvents, at a temperature of between xe2x88x9270xc2x0 C. and ambient temperature.
The 1H-indole-2,3-dione derivatives (VIII) are commercially available or prepared according to the methods described in Tetrahedron Letters, 199,8, 39, 7679-7682; Tetrahedron Letters, 1994, 35, 7303-7306; J. Org. Chem., 1977, 42 (8), 1344-1348; J. Org. Chem., 1952, 17, 149-156; J. Am. Chem. Soc., 1946, 68, 2697-2703, Organic Syntheses, 1925, V, 71-74 and Advances in Heterocyclic Chemistry, A. R. Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58.
The organomagnesium derivatives (IX) are prepared according to conventional methods well known to a person skilled in the art.
A compound of formula (VI) can also be prepared by air oxidation of a compound of formula (VII) in the presence of a base, such as sodium hydride, and in the presence of dimethyl disulphide.
Specifically, the compounds of formula (VI) in which R3=(C1-C2)alkoxy and R4=H or else R3xe2x95x90R4=(C1-C2)alkoxy with R4 in the 3- or 6-position of the phenyl, R2 is other than a halogen atom and R1 is as defined for a compound of formula (I) can be prepared by following the process described in SCHEME 1. 
In stage a1 of SCHEME 1, a compound of formula (X) is first of all reacted with a lithium derivative, such as n-butyllithium, in the absence or in the presence of a base, such as N,N,Nxe2x80x2,Nxe2x80x2-tetramethylenediamine, and then the lithiated intermediate thus obtained is reacted with diethyl oxalate to give the compound of formula (XI). The reaction is carried out in an inert solvent, such as diethyl ether or tetrahydrofuran, and at a temperature of between xe2x88x9270xc2x0 C. and ambient temperature.
In stage b1, a compound of formula (XII) is first of all reacted with two equivalents of a lithium derivative, such as tert-butyllithium, and then the lithiated intermediate obtained is reacted with the compound of formula (XI) to give the expected compound of formula (VI). The reaction is carried out in an inert solvent, such as diethyl ether or tetrahydrofuran, and at a temperature of between xe2x88x9270xc2x0 C. and ambient temperature.
The compounds of formula (X) are commercially available or are synthesized in a conventional way.
The compounds of formula (XII) are prepared by reaction of the corresponding aniline derivatives with di-tert-butyl dicarbonate according to conventional methods.
The compounds of formula (VII) are known and are prepared according to known methods, such as those disclosed in WO 95/18105 or in J. Org. Chem., 1968, 33, 1640-1643.
The compounds of formula (V) are known or are prepared according to known methods. Thus, for example, the compounds of formula (V) in which R5 represents an ethylamino or dimethylamino group or an azetidin-1-yl radical are prepared according to SCHEME 2 below, in which Pr represents an N-protecting group, in particular tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl, and n, p, R8 and R9 are as defined for a compound of formula (I). 
In stage a2 of SCHEME 2, the nitrogen atom of the compound of formula (XIII) is protected according to conventional methods to obtain a compound of formula (XIV). Some of the compounds of formula (XIV) are commercially available.
The acid (XIV) is reacted in stage b2 with ethylamine, dimethylamine or azetidine according to conventional peptide coupling methods to give the compound of formula (XV), which is deprotected in stage c2 according to known methods to give the expected compound of formula (V). In particular, when Pr represents a 9-fluorenylmethoxycarbonyl group, deprotection is carried out using the method described in Synthetic Communications, 1994, 24 (2), 187-195.
The compounds of formula (V) in which R5 represents a (C1-C2)alkoxy are known or are prepared according to known methods, such as, for example, by an esterification reaction starting with the acids of formula (XIII), or according to the methods described in Tetrahedron Letters, 1986, 27, 2409-2410; J. Am. Chem. Soc., 1970, 92, 2476-2488; Tetrahedron Asymmetry, 1998, 9, 4295-4299; J. Med. Chem., 1994, 37, 3956-3968; J. Chem. Soc. Perkin Trans 1, 1977, 596-600; Gazz. Chim. Ital., 1976, 106, 65; Chem. Pharm. Bull., 1983, 31, 312-314; J. Med. Chem., 1983, 26, 1267-1277; J. Org. Chem., 1997, 62, 7679-7689; J. Med. Chem., 1992, 35, 1942-1953; Justus Liebigs Ann. Chem., 1976, 367-382; J. Org. Chem., 1978, 43, 2115-2119; Tetrahedron Letters, 1997, 38, 6977-6980; Helv. Chim. Acta, 1959, 42, 2431-2436.
The acids of formula (XIII) are commercially available or are prepared according to known methods. Thus, for example:
2,3-Dihydro-1H-indole-2-carboxylic acids are prepared according to J. Med. Chem., 1983, 26, 394-403; Agric. Biol. Chem., 1987, 51, 1833-1838; J. Med. Chem., 1983, 26, 1267-1277; Helv. Chim. Acta, 1962, 45, 638; Helv. Chim. Acta, 1968, 51, 1476.
1,2,3,4-Tetrahydroquinoline-2-carboxylic acids are prepared according to J. Org. Chem., 1990, 55, 738-741; J. Med. Chem., 1992, 35, 1942-1953;
Isoindoline-1-carboxylic acids are prepared according to J. Heterocyclic. Chem., 1984, 21, 1355-1360;
1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acids are prepared according to Synthesis, 1992, 11, 1157-1160; Int. J. Peptide Protein Res., 1994, 43, 62-68; Liebigs Ann./Recueil, 1997, 3, 533-540; J. Med. Chem., 1988, 31, 2092-2097; J. Chem. Soc., 1938, 172-175; J. Chem. Soc., 1950, 1534-1537; Synthesis, 1990, 550-556; Heterocycles, 1992, 34, 757-764; J. Med. Chem., 1983, 26, 1267-1277;
1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acids are prepared according to J. Med. Chem., 1993, 36, 314-319 or according to WO 93/12091.
When it is desired to prepare an optically pure compound of formula (I), an optically pure compound of formula (II) is preferably reacted with a compound of formula (III) according to the process of the invention.
The optically pure compounds of formula (II) are prepared by reaction of the racemic compound of formula. (IV) with an optically pure compound of formula (V), followed by separation of the mixture of diastereoisomers according to conventional methods, for example by crystallization or chromatography.
Alternatively, the mixture of diastereoisomers of the compound of formula (II) can be reacted with the compound of formula (III) and the mixture of diastereoisomers of the compound of formula (I) thus obtained can be separated.
During any one of the stages for the preparation of the compounds of formula (I) or of the intermediate compounds of formula (II), (IV), (V) or (VI), it may be necessary and/or desirable to protect the reactive or sensitive functional groups, such as amine, hydroxyl or carboxyl groups, present on any one of the molecules concerned. This protection can be achieved by using conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, J. F. W. McOmie, published by Plenum Press, 1973, in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wutts, published by John Wiley and Sons, 1991 or in Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag. The protecting groups can be removed at an appropriate subsequent stage using methods known to a person skilled in the art which do not affect the remainder of the molecule concerned.
The N-protecting groups optionally used are conventional N-protecting groups well known to a person skilled in the art, such as, for example, the tert-butoxycarbonyl, fluorenylmethoxycarbonyl, benzyl, benzhydrylidene or benzyloxycarbonyl group.
The compounds of formula (II) are novel and form part of the invention.
Thus, according to another of its aspects, a subject-matter of the invention is compounds of formula: 
in which:
n is 0, 1 or 2 and p is 0, 1 or 2; the sum n+p being equal to 1 or 2;
R1 represents a halogen atom; a (C1-C4) alkyl; a (C1-C4)alkoxy; a trifluoromethyl radical; or a trifluoromethoxy radical;
R2 represents a hydrogen atom; a halogen atom; a (C1-C4)alkyl; a (C1-C4)alkoxy; or a trifluoromethyl radical;
or else R2 is in the 6-position of the indol-2-one ring and R1 and R2 together represent the bivalent trimethylene radical;
R3 represents a halogen atom; a hydroxyl; a (C1-C2)alkyl; a (C1-C2)alkoxy; or a trifluoromethoxy radical;
R4 represents a hydrogen atom; a halogen atom; a (C1-C2) alkyl; or a (C1-C2) alkoxy;
or else R4 is in the 3-position of the phenyl and R3 and R4 together represent the methylenedioxy radical;
R5 represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; or a (C1-C2) alkoxy;
R8 represents a hydrogen atom; a halogen atom; a (C1-C4) alkyl; or a (C1-C4) alkoxy;
R8 represents a a hydrogen atom; a halogen atom; a (C1-C4) alkyl; or a (C1-C4) alkoxy;
and their salts with inorganic or organic acids, in the form of optically pure isomers or in the form of a mixture of diastereoisomers or in the form of a racemic mixture.
The salts of the compounds of formula.(II) comprise those with inorganic or organic acids which make possible suitable separation or crystallization of the compounds of formula (II), such as the hydrochloride, hydrobromide, oxalate, maleate, succinate, fumarate, citrate or acetate.
The compounds of above formula (I) also comprise those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium or carbon-14. Such labelled compounds are of use in research, metabolism or pharmacokinetic studies or in biochemical assays as receptor ligand.
The compounds according to the invention have formed the subject of biochemical studies.
The affinity of the compounds of formula (I) according to the invention for arginine-vasopressin V1b receptors was determined in vitro by using the method described by Y. De Keyser et al., FEBS Letters, 1994, 356, 215-220. This-method consists in studying in vitro the displacement of tritiated arginine-vasopressin ([3H]-AVP) at the V1b receptors present on adenohypophysal membrane or cell preparations carrying rat or human V1b receptors. The 50% inhibitory concentrations (IC50) for the attachment of tritiated arginine-vasopressin of the compounds according to the invention are low and vary from 10xe2x88x926 to 10xe2x88x929M, more particularly from 10xe2x88x927 to 10xe2x88x929M.
The affinity of the compounds of formula (I) according to the invention for arginine-vasopressin V1a receptors was determined in vitro using the method described by M. Thibonnier et al., J. Biol. Chem., 1994, 269, 3304-3310. This method consists in studying in vitro the displacement of tritiated arginine-vasopressin ([3H]-AVP) at the V1a receptors present on membrane or cell preparations carrying rat or human V1a receptors. Some of the compound of formula (I) also exhibit an affinity for arginine-vasopressin V1a receptors, with IC50 values which vary from 10xe2x88x926 to 10xe2x88x929M, more particularly from 10xe2x88x927 to 10xe2x88x928M.
The affinity of the compounds of formula (I) according to the invention for vasopressin V2 receptors has also been studied (method described by M. Birnbaumer et al., Nature (Lond.), 1992, 357, 333-335). The compounds studied have little or no affinity for the V2 receptors.
The compounds of the present invention are in particular active principles of pharmaceutical compositions, the toxicity of which is compatible with their use as medicaments.
According to another of its aspects, the present invention relates to the use of the compounds of formula (I), of their solvates and/or of their hydrates which are pharmaceutically acceptable for the preparation of medicaments intended for the treatment of any pathology where arginine-vasopressin and/or its V1b receptors or both its V1b receptors and its V1a receptors are implicated.
According to another of its aspects, the present invention relates to the use of the compounds of formula (I), of their solvates and/or of their hydrates which are pharmaceutically acceptable in the preparation of medicaments intended for the treatment of pathologies of the cardiovascular system, of the central nervous system, of the renal system or of the gastric system and of small cell lung cancers, obesity, type-II diabetes, insulin resistance, hypertriglyceridaemia, atherosclerosis, Cushing""s syndrome or any pathology resulting from stress and chronic stress conditions.
Thus, the compounds according to the invention may be used, in man or in animals, in the treatment or prevention of various vasopressin-dependent conditions, such as cardiovascular conditions, for example hypertension, pulmonary hypertension, cardiac insufficiency, myocardial infarction or coronary vasospasm, in particular in smokers, Raynaud""s syndrome, unstable angina and PTCA (percutaneous transluminal coronary angioplasty), cardiac ischaemia or haemostasis disturbances; conditions of the central nervous system, such as migraine, cerebral vasospasm, cerebral haemorrhage, cerebral oedema, depression, anxiety, stress, obsessive-compulsive disorder, panic attacks, psychotic states or memory disorders, for example; conditions of the renal system, such as renal vasospasm, necrosis of the renal cortex or nephrogenic diabetes insipidus; conditions of the gastric system, such as gastric vasospasm, cirrhosis of the liver, ulcers or the pathology of vomiting, for example nausea, including nausea due to chemotherapy or travel sickness; or diabetic nephropathy. The compounds according to the invention can also be used in the treatment of disorders of sexual behaviour; in women, the compounds according to the invention can be used to treat dysmenorrhoea or premature labour. The compounds according to the invention can also be used in the treatment of small cell lung cancers; hyponatremic encephalopathy; pulmonary syndrome; Mxc3xa9nixc3xa8re""s disease; glaucoma; cataracts; obesity; type-II diabetes; atherosclerosis; Cushing""s syndrome; insulin resistance; or hypertriglyceridaemia; or in post-operative treatments, in particular after abdominal surgery.
The compounds according to the invention can also be used in the treatment or prevention of any pathology resulting from stress, such as fatigue and its syndromes, ACTH-dependent disorders, cardiac disorders, pain, modifications in gastric emptying, in faecal excretion (colitis, irritable bowel syndrome or Crohn""s disease) or in acid secretion, hyperglycaemia, immunosuppression, inflammatory processes (rheumatoid arthritis and osteoarthritis), multiple infections, cancers, asthma, psoriasis, allergies and various neuropsychiatric disorders, such as anorexia nervosa, bulimia, mood disorders, depression, anxiety, sleep disorders, panic states, phobias, obsession, disorders of pain perception (fibromyalgia), neurodegenerative diseases (Alzheimer""s disease, Parkinson""s disease or Huntington""s disease), substance dependence, haemorrhagic stress, muscle spasms or hypoglycaemia. The compounds according to the invention can also be used in the treatment or prevention of chronic stress conditions, such as immunodepression, fertility disorders or dysfunctionings of the hypothalamopituitaryadrenal axis.
The compounds according to the invention can also be used as psychostimulants, resulting in an increase in alertness or emotional reactivity to the surroundings and making adaptation easier.
The compounds of above formula (I), their solvates and/or their hydrates which are pharmaceutically acceptable can be used at daily doses of 0.01 to 100 mg per kilo of body weight of the mammal to be treated, preferably at daily doses of 0.1 to 50 mg/kg. In man, the dose can preferably vary from 0.1 to 4000 mg per day, more particularly from 0.5 to 1000 mg, depending upon the age of the subject to be treated or the type of treatment; prophylactic or curative.
For their use as medicaments, the compounds of formula (I) are generally administered in dosage units. The said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with one or more pharmaceutical excipients.
Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions including, as active principle, a compound of formula (I), one of its solvates and/or one of its hydrates which are pharmaceutically acceptable.
In the pharmaceutical compositions of the present invention for administration by the oral, sublingual, inhaled, subcutaneous, intramuscular, intravenous, transdermal, local or rectal route, the active principles can be administered in single-dose administration forms, as a mixture with conventional pharmaceutical vehicles, to animals and human beings. The appropriate single-dose administration forms comprise forms by the oral route, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, topical administration forms, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
When a solid composition is prepared in the form of tablets or gelatin capsules, a mixture of pharmaceutical excipients is added to the micronized or nonmicronized active principle, which mixture can be composed of diluents, such as, for example, lactose, microcrystalline cellulose, starch or dicalcium phosphate, of binders, such as, for example, polyvinylpyrrolidone or hydroxypropylmethylcellulose, of disintegrating agent, such as crosslinked polyvinylpyrrolidone or crosslinked carboxymethylcellulose, of flow agents, such as silica or talc, or of lubricants, such as magnesium stearate, stearic acid, glyceryl tribehenate or sodium stearylfumarate.
Wetting agents or surfactants, such as sodium lauryl sulphate, polysorbate 80 or poloxamer 188, can be added to the formulation.
The tablets can be prepared by various techniques: direct tableting, dry granulation, wet granulation or hot-melt.
The tablets can be bare or sugar-coated (with sucrose, for example) or coated with various polymers or other appropriate materials.
The tablets can have a flash, delayed or sustained release by preparing polymeric matrices or by using specific polymers when forming the thin film.
The gelatin capsules may be soft or hard and may or may not be coated with a thin film, so as to have a flash, sustained or delayed activity (for example via an enteric form).
They can comprise not only a solid formulation formulated as above for tablets but also liquids or semi-solids.
A preparation in the form of a syrup or elixir can comprise the active principle in conjunction with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben, as antiseptic, a flavouring agent and an appropriate colorant.
The water-dispersible powders or granules can comprise the active principle as a mixture with dispersing agents, wetting agents or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavour enhancers.
For rectal administration, recourse is had to suppositories which are prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
For parenteral, intranasal or intraocular administration, use is made of aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which comprise pharmacologically compatible dispersing agents and/or solubilizing agents, for example propylene glycol.
Thus, to prepare an aqueous solution which can be injected by the intravenous route, use may be made of a cosolvent, such as, for example, an alcohol, such as ethanol, or a glycol, such as polyethylene glycol or propylene glycol, and of a hydrophilic surfactant, such as polysorbate 80 or poloxamer 188. To prepare an oily solution which can be injected by the intramuscular route, the active principle can be dissolved with a triglyceride or a glyceryl ester.
For local administration, use may be made of creams, ointments, gels, eyewashes or sprays.
For transdermal administration, use may be made of patches in multilaminar or reservoir form, in which the active principle can be in alcoholic solution, or sprays.
For administration by inhalation, use is made of an aerosol comprising, for example, sorbitan trioleate or oleic acid and trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane, freon substitutes or any other biologically compatible propellant gas; use may also be made of a system comprising the active principle, alone or in combination with an excipient, in powder form.
The active principle can also be presented in the form of a complex with a cyclodextrin, for example xcex1, xcex2- or xcex3-cyclodextrin or 2-hydroxypropyl-xcex2-cyclodextrin.
The active principle can also be formulated in the form of microcapsules or microspheres, optionally with one or more vehicles or additives.
Use may be made of implants among the sustained-release forms of use in the case of chronic treatments. These implants can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
The active principle of formula (I) is present in each dosage unit in the amounts suited to the daily doses envisaged. In general, each dosage unit is suitably adjusted according to the dosage and the type of administration provided, for example tablets, gelatin capsules and the like, sachets, blisters, syrups and the like, or drops, so that such a dosage unit comprises from 0.1 to 1000 mg of active principle, preferably from 0.5 to 250 mg, which has to be administered one to four times daily.
Although these dosages are examples of average situations, there may be specific cases where higher or lower dosages are appropriate; such dosages also form part of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the method of administration and the age, the weight and the response of the said patient.
The compositions of the present invention can comprise, in addition to the compounds of formula (I), their solvates and/or their hydrates which are pharmaceutically acceptable, other active principles which can be of use in the treatment of the disorders or diseases indicated above.
Thus, another subject-matter of the present invention is pharmaceutical compositions comprising several active principles in combination, one of which is a compound according to the invention.
Thus, according to the present invention, pharmaceutical compositions can be prepared which comprise a compound according to the invention in combination with a compound which has an effect on the CRF receptors.
The compounds according to the invention can also be used for the preparation of compounds for veterinary use.